ABSTRACT In developed countries, age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly and there are no treatments for the majority of patients. Early AMD is characterized by the formation of protein- and lipid-rich, sub-retinal pigmented epithelium (RPE) deposits. These deposits contain many constituents that are attributable to both the activation of the complement cascade and lipoprotein metabolism. In addition, complement and lipoprotein pathway genes have been independently associated with AMD in multiple ways including genetic risk association and epidemiological studies. Efforts to understand how lipid metabolism/trafficking and complement dysregulation contribute to AMD have been limited in part by the lack of age-dependent in vivo models that faithfully recapitulate these pathogenic aspects of the disease. The aim of the proposed studies is to leverage data derived using novel animal models of AMD that we have developed. These models invoke advanced age, complement dysregulation and lipid/cholesterol perturbation, all known contributors to human AMD risk. Specifically, we generated mouse models based on the most replicated genetic risk variant associated with AMD risk, the tyrosine (Y) to histidine (H) substitution at amino acid position 402 (Y402H) of human complement factor H, the soluble regulator of the alternative complement pathway. Only mice expressing the human H402 AMD risk variant (CFH-H/H) develop an AMD phenotype compared to mice expressing the normal human Y402 CFH variant. Significantly, the AMD phenotype correlates with changes in lipoprotein levels in blood, and in the RPE/Bruch?s membrane (BrM)/choroid complex. Thus, we are the first to observe a functional consequence of the Y402H polymorphism in vivo, which promotes an AMD-like pathology and affects lipoprotein levels in aged mice. In addition, we analyzed ApoA-1 containing lipoproteins isolated from BrM and plasma of elderly human donors and found they have very different protein compositions. The most striking difference is the significantly higher concentration of ApoB and ApoE in BrM, which are known to bind to glycosaminoglycans (GAGs) and could promote lipoprotein deposition onto BrM GAGs; likely initiating downstream effects that contribute to RPE dysfunction/death. Based on these observations and other studies we hypothesize that aberrant RPE-derived high-density lipoprotein (HDL)-like lipoprotein secretion contributes to AMD development, and is modulated by CFH. Thus, the goals of the proposed studies are to use our novel animal models of AMD and human induced pluripotent stem cell-derived RPE to (1) elucidate the mechanism by which CFH modulates lipoprotein clearance in AMD pathogenesis and (2) to test whether augmenting normal CFH and/or enhancing local HDL clearance are viable strategies for treating AMD. Outcomes from these studies will mechanistically determine the interaction of two risk factors, CFH and lipoproteins in AMD and establish proof of concept for these factors as therapeutic targets for AMD.